In the BB rat model, the expression of CLDN1, one of the main sealing claudins of the intestine, was lower compared to controls at all investigated time points, also at 30 days when the permeability parameters were still similar in both strains. The reason for lower CLDN1 expression is unclear, but it may represent a genetic susceptibility. Our data are in partial agreement with Visser et al. who reported decreased CLDN1 expression in the ileum of 50 to 70 day old BB-DP rats, but not at 30–50 days. It is unclear whether regional variation, i.e. jejunum vs. ileum, or a different substrain may explain the difference in time of onset. A lower expression of CLDN1 has also been reported in one study in patients with diarrhea-predominant IBS, although not confirmed by others. Only from the age of 50 days, intestinal permeability increased in BB-DP animals, coinciding with an enhanced expression of CLDN2, a pore-forming claudin that enhances permeability. Combined, these data suggest that in our model lower expression of CLDN1 is insufficient to induce increased permeability and only the combination with increased CLDN2, of which the trigger has not been identified yet, leads to the barrier defect. Increased expression of CLDN2 has also been reported in intestinal biopsies of patients with IBD and IBS. However, the exact mechanisms by which the overexpression of CLDN2 can contribute to disease pathogenesis are still elusive since only small, supposedly non-immunogenic, solutes can permeate through CLDN2 pores. Intriguingly, the mucosal-toserosal flux of the 20 kDa dextran was unchanged at 50 days, while a clear decrease in TEER was present. At the later time points, a progressive rise in dextran passage was observed, in contrast to a stable difference in TEER. At least two different routes of intestinal paracellular flux have been reported in literature: a large-capacity pathway for small solutes and water, the ‘pore pathway’, and a small-capacity pathway for larger molecules, the ‘leak pathway’. The mucosal-toserosal flux of macromolecules is regulated by the leak pathway, while TEER reflects a combination of both pore and leak pathway. Although cross-talk exists to some extent, both pathways are regulated separately. Our data suggest that the pore pathway is affected first in BB-DP animals, while the defect in the leak pathway only follows at later time points. However, we cannot exclude that the size of the dextran used in our BI-D1870 experiments prevented us from detecting early differences in the leak pathway. The combination of different sizes of tracers could help to answer this question, which, however, was beyond the scope of the current study. The observed alterations in permeability and the fact that inflammation progresses over time from the mucosa to the muscle layer, point towards the involvement of a luminal factor. Previous studies have supported this hypothesis.